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Chromoanagenesis event underlies a de novo pericentric and multiple paracentric inversions in a single chromosome causing Coffin-Siris Syndrome

ABSTRACT: Chromoanagenesis event underlies a de novo pericentric and multiple paracentric inversions in a single chromosome causing Coffin-Siris Syndrome

PROVIDER: PRJNA748144 | ENA |

REPOSITORIES: ENA

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Chromoanagenesis event underlies a de novo pericentric and multiple paracentric inversions in a single chromosome causing Coffin-Siris Syndrome

Project description:Chromoanagenesis is a descriptive term that encompasses classes of catastrophic mutagenic processes that generate localized and complex chromosome rearrangements in both somatic and germline genomes. Herein we describe a 5-year-old female presenting with a constellation of clinical features consistent with a clinical diagnosis of Coffin-Siris syndrome 1 (CSS1). Initial G-banded karyotyping detected a 90 Mb pericentric and 47 Mb paracentric inversion on a single chromosome. Subsequent analysis using short-read whole genome sequencing, and genomic optical mapping revealed additional inversions, all clustered on chromosome 6, one of them disrupting ARID1B for which haploinsufficiency leading to CSS1. In all, the resolved derivative chromosome architecture presents four de novo inversions, one pericentric and three paracentric, involving six breakpoint junctions in what appears to be a shuffling of genomic material on this chromosome. Each junction was resolved to nucleotide-level resolution with mutational signatures suggestive of non-homologous end joining. The disruption of the gene ARID1B is shown to occur between the 4th and 5th exon of the canonical transcript with subsequent qPCR studies confirming a decrease in ARID1B expression in the patient versus healthy controls. Deciphering the underlying genomic architecture of chromosomal rearrangements and complex structural variants may require multiple technologies and can be critical to elucidating the molecular etiology of a patient’s clinical phenotype or resolving unsolved Mendelian disease cases.

2021-07-22 | GSE180423 | GEO

Project description:Chromoanagenesis event underlies a de novo pericentric and multiple paracentric inversions in a single chromosome causing Coffin-Siris Syndrome

| PRJNA748013 | ENA

Chromoanagenesis Event Underlies a <i>de novo</i> Pericentric and Multiple Paracentric Inversions in a Single Chromosome Causing Coffin-Siris Syndrome.

Project description: Not available

| S-EPMC8427664 | biostudies-literature

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders

Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.

2021-10-12 | PXD028557 | Pride

Are Pericentric Inversions Reorganizing Wedge Shell Genomes?

Project description: Not available

| S-EPMC5748688 | biostudies-literature

Silencing of pericentric heterochromatin associated with SIRT6-dependent H3K18 deacetylation protects against mitotic errors and cellular senescence

Project description:Pericentric heterochromatin silencing at mammalian centromeres is essential for mitotic fidelity and genomic stability. Defective pericentric silencing is observed in senescent cells, aging tissues, and mammalian tumors, but the underlying mechanisms and functional consequences of these defects are unclear. Here, we uncover a pivotal role of the human SIRT6 enzyme in pericentric transcriptional silencing, and this function protects against mitotic defects, genomic instability, and cellular senescence. At pericentric heterochromatin, SIRT6 promotes deacetylation of a new substrate, histone H3 lysine K18 (H3K18), and inactivation of SIRT6 in cells leads to H3K18 hyperacetylation and aberrant accumulation of pericentric transcripts. Strikingly, RNAi-depletion of these transcripts rescues the mitotic and senescence phenotypes of SIRT6-deficient cells. Together, our findings reveal a new function for SIRT6 and H3K18Ac regulation at heterochromatin, and demonstrate the pathogenic role of de-regulated pericentric transcription in aging- and cancer- related cellular dysfunction. H3K18ac, H3K9ac, H3K9me3, H3K56ac and Input ChIP-seq for U2OS cell

2016-04-04 | E-GEOD-69809 | biostudies-arrayexpress

Silencing of pericentric heterochromatin associated with SIRT6-dependent H3K18 deacetylation protects against mitotic errors and cellular senescence

2016-04-04 | GSE69809 | GEO

Transcription profiling by array of four strains of budding yeast with inversions engineered between TY1 elements against matching controls

Project description:Gene expression changes due to genome region inversions was studied. Four strains of Saccharomyces cerevisiae strains with inversions engineered between TY1 elements were compared to matching controls.

2014-11-05 | E-MTAB-2613 | biostudies-arrayexpress

Expression differences between inversions and their progenitors in Drosophila melanogaster

Project description:Inversions have a breakpoint within a "neighbourhood" of testis expressed genes and the other breakpoint megabases away. The gene expression neighbourhood is therefore intact in the progenitor but disrupted in the inversion. 12 different inversion stocks, 3 or 4 biological replicates for each, including dye swaps.

2010-06-25 | E-GEOD-16616 | biostudies-arrayexpress

Expression differences between inversions and their progenitors in Drosophila melanogaster

2010-12-06 | GSE15565 | GEO

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